JPS6234733B2 - - Google Patents

Description

[Detailed description of the invention]

BACKGROUND OF THE INVENTION The present invention relates to compositions for inhibiting the development of acute radiation syndrome caused by exposing warm-blooded animals to systemic doses of X-rays of about 100 radians.
The present invention also relates to compositions for inhibiting the development of sepsis. Their expression is inhibited by administering to warm-blooded animals an effective amount of these compositions comprising purified, detoxified endotoxin (RDE) together with a pharmaceutically acceptable carrier. When warm-blooded animals are exposed to whole-body doses of x-rays of at least about 100 radians, they develop a complex group of symptoms called acute radiation syndrome. The nature and severity of acute radiation syndrome can vary greatly from exposure to warm-blooded animals.
Directly related to the amount of lines. However, it is generally accepted that the hematopoietic system, which is responsible for the production of blood cells, is most severely damaged. Part 1: Destruction of the blood hypertrophic system due to high-level radiation exposure
One of the most important consequences is that antimicrobial immunity is severely impaired against both exogenous and endogenous microorganisms. High levels of X-ray radiation cause all warm-blooded animals, including humans, to experience "Beneficial Effects of Endotoxings".
Edited by Alois Nowatny, pp. 127-148, Plenum
Press, 1983, it is susceptible to a wide range of bacteria, viruses, protozoa, etc. In order to counteract the harmful effects of X-rays, it is necessary to stimulate the production and differentiation of granulocytes (granulopoiesis). Granulocytes are white blood cells such as macrophages, monocytes, eosinophils and basophils. The blood is
It is known to contain a factor known as colony-stimulating factor (CSF), which is necessary for granulopoiesis. Colony-stimulating factors are described in Science 118, p. 164 (1972) by Chervenich PA and Lancet 2, 1397 (1972) by Golde, DW. )It is described in. Therefore, the extent to which blood exhibits colony-stimulating factors is directly related to its ability to withstand high doses of radiation. Sepsis is a clinical syndrome in which infection spreads through the body by the bloodstream. This is a serious blood infection that can be caused by a variety of bacteria. This is a pathological condition due to the presence of microorganisms and/or their harmful by-products in the bloodstream. A 1974 study reported that 71,000 people in the United States contract sepsis each year, and about 25% of them die. One of the major causes of sepsis is post-surgical infection due to endogenous bacteria from the respiratory or gastrointestinal tract (Cruse, PJE), Surgical Record (Arch., Surg.)
107, pp. 106-210, 1973). Purified and detoxified endotoxin (RDE)
No detectable 2-keto-3-deoxyoctanoate, about 350-470 nmol/mg phosphorus and about
It is characterized by containing 1700 to 2000 nmol/mg of fatty acids. RDE has clear protection against endotoxin extracts obtained from Enterobacteriaceae, as it is detoxified and therefore does not contain highly toxic components that would make endotoxin extracts unsuitable for therapeutic use. Peptides as Requirements for Immunotherapy with Endotoxin for Guinea Pig Line-10 Tumors
Immunotherapy of the Guinea－Pig Line－
10Tumor with Endotoxins) Outside Ribi
Cancer Immunol. Immunother, Vol. 7, pp. 43-58.
1979). The beneficial effects of RDE on other endotoxin extracts have been demonstrated, for example, in US Pat. No. 4,436,727 and
4436728, and E. Ribi (E.) Journal
Journal of Biological Response Modification Years
Modifiers) 3:1-9, Raven Press (1984
year). Accordingly, it is an object of the present invention to obtain a purified product which is suitable for inhibiting the development of acute radiation syndrome in warm-blooded animals exposed to a systemic dose of X-rays of at least about 100 radians or for inhibiting the development of sepsis in warm-blooded animals. An object of the present invention is to provide a therapeutic composition containing detoxified endotoxin. SUMMARY OF THE INVENTION The present invention provides a method for (1) suppressing the development of acute radiation syndrome in warm-blooded animals caused by exposing the warm-blooded animals to a systemic dose of at least 100 radians, or (2) The present invention provides a composition capable of inhibiting the development of sepsis in patients, the composition comprising a therapeutically effective amount of (a) detectable 2-keto-3-deoxyoctanoate; about 350 to 475 nmol/mg of sulfur and about 1700 to 2000 nmol/mg of fatty acids,
(b) a pharmaceutically acceptable carrier. DETAILED DESCRIPTION OF THE INVENTION Purified and detoxified endotoxins used in the present invention can be prepared by the methods described in US Pat. Nos. 4,436,727 and 4,436,728. More particularly, endotoxin extracts of the type used as starting materials for producing RDEs are obtained from the family Enterobacteriaceae, including original and mutant forms of microorganisms. The above patents describe the types of microorganisms that can be used to obtain the starting materials and several methods for producing the starting materials. The preferred method for obtaining endotoxin extract is Chen
Outside, J. Infect. Dis (J.Infect.Dis) 128
Vol., p. 543) (1973). The RDE prepared as described above may be prepared in a pharmaceutically acceptable carrier such as, for example, a phosphate buffered saline solution that can be injected parenterally (e.g., intravenously, intraperitoneally, or intramuscularly). be brought together. This composition is suitable for normal body weight
For administration to a 70Kg adult patient, approximately 1 to
1000 micrograms, preferably about 25-200 micrograms of RDE. The composition can be administered to a patient once, twice or three times per week, and the number of doses is usually about two to three times. When used to suppress the onset of acute radiation syndrome, the RDE-containing composition is administered for at least about 24 hours, preferably about 24 hours, before a warm-blooded animal is exposed to a high radiation dose of at least about 100 radians.
Should be administered for ~48 hours. The present invention will be further explained below with reference to Examples. Example 1 Colony stimulating factor (CSF) in vivo
Three groups of NMRI mice (each group containing 5 mice) were each injected intravenously with 5 micrograms of the test substances listed in Table 1 below.

[Table] * Arithmetic mean Orbital plexus (Plexus) 2 hours after blood injection
orbitalis) and then assayed three times to determine the CSF content. The assay method was developed by D. Metcalf (D.) and M.A. Moore (Moore, MA).
Cells), North Holland Publishing Company,
Amsterdam, Netherlands, 1971). CSF content was expressed as the number of colonies in 10 ⁵ nucleated bone marrow cells per ml. As shown in Table 1, the two groups of mice injected with RDE showed obvious CSF activity, whereas the control group injected with saline solution only did not show CSF activity. This study reveals that RDE stimulates the production of CSF, which is necessary for the generation and differentiation of granulocytes (granulopoiesis). Example 2 Protection against X-rays Two groups of C3HeB/FeJ mice (each group
(consisting of 20 mice) were injected intravenously with the test substances shown in Table 2. These mice are 70
It was injected 24 hours prior to irradiation with 600 rad of X-rays at a rate of rad/min. A third group of 20 mice (control) was not injected with the test substance and was irradiated in the same way as the two groups of mice described above. As shown in A. Nowatny, A., p. 127, peak mortality for sublethal doses of X-rays occurs 10-14 days after irradiation. Therefore, it was expected that both control animals and animals treated with RDE prior to irradiation would survive the first 10 days after irradiation with such high levels of radiation. After 15 days, 85% of the RDE-treated animals survived, while only 55% of the control animals survived. 20 days after irradiation, RDE
70-75% of treated mice survived, whereas only 25% of control animals survived. Therefore, RDE is an effective factor in reducing the risk of death after exposure to high levels of radiation.

[Table] Example 3 Protection against development of sepsis Fourteen NMRI mice were treated with 1 microgram
RDE was pretreated by administering it by intraperitoneal injection. After 24 hours, each mouse was operated on and each mouse's cecum was ligated and punctured to internally expose the mouse to microorganisms capable of inducing episodes of sepsis. After completion of surgery, animals were incubated at 120
I observed the time. A second group of mice was operated in exactly the same way without pretreatment with RDE. The results are shown in Table 3. 71% of RDE-treated mice survived 120 hours after induction of sepsis. Only 21% of mice not pretreated with RDE survived. These results indicate that RDE suppresses the development of sepsis.

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Claims (1)

[Scope of Claims] 1. (1) Suppressing the development of acute radiation syndrome in warm-blooded animals caused by exposing the warm-blooded animals to X-rays at a systemic dose of at least 100 radians, or (2)
A composition capable of inhibiting the development of sepsis in a warm-blooded animal, the composition comprising: (a) free of detectable 2-keto-3-deoxyoctanoate; containing 475 nmol/mg sulfur and about 1700-2000 nmol/mg fatty acids,
A composition comprising: a purified, detoxified endotoxin; and (b) a pharmaceutically acceptable carrier. 2. The composition of claim 1 in the form of a phosphate buffered saline solution.